One of the main objectives of this project is to understand the mechanisms of neuritic plaque formation in the Alzheimer's disease (AD) brain. In order to acomplish this goal we are developing transgenic animal models of AD in the rodent as well as studying AD brain biopsy material with the IVEM and the confocal microscope. The two most extensively characterized alterations in AD are the deposition of an insoluble form of amyloid 13 protein, derived from the abnormal processing of amyloid precursor protein, and the abnormal phosphorylation of cytoskeletal and growth associated proteins. Structurally, these molecular alterations are associated with a severe cytoskeletal disruption of neurites in the neocortex accompanied by an extensive synaptic loss. The classical view of the AD plaque derived from 2D images is that neuritic alterations are distributed in the periphery of the plaque, with the insoluble form of amyloid 13 protein localized in the plaque core. A 3-D analysis of plaque components was performed in semi-thin sections viewed with IVEM and in reconstructions obtained from confocal microscopy and serial electron micgraphs. Rotating movie loops created using Synu showed that in two thirds of the plaques, the great majority of the of the plaque volume was occupied by clustered and continuous abnormal neurites while the amyloid fibrils were compressed and displaced to the periphery of the plaque. This analysis suggests a more widespread and active neuritic damage than that predicted from 3-D observations and supports a theory in which synapto-axonal damage plays an important role in the pathogenesis of the plaque. This view is supported by more recent ultrastructural studies in transgenic animals.